ES2223291B1 - NEW THERAPEUTIC USE OF CONDROITIN SULFATE. - Google Patents

Abstract

New therapeutic use of chondroitin sulfate. The present invention relates to the use of alkali metal or alkaline earth metal chondroitin sulfate, which comes from an enzymatic hydrolysis of animal cartilage, for the treatment of psoriasis with dermal involvement in a mammal. Preferably, sodium chondroitin sulfate has an average molecular weight between 10,000 and 20,000 daltons, and is administered orally.

Description

New therapeutic use of chondroitin sulfate.

Technical sector of the invention

The present invention relates to the use of Chondroitin alkali metal or alkaline earth metal sulfate, which comes of an enzymatic hydrolysis of animal cartilage, for treatment or prevention of psoriasis with involvement dermal

Background of the invention

Psoriasis with dermal involvement has a great clinical polymorphism (E. Christophers, Clin. Exp. Dermatol. 26 (4), 314-320 (2001)). Clinically, the skin lesion manifests itself in the form of an erythematous plaque with net edges, covered by thick, whitish, waxy-looking scales, which are preferably distributed by extension areas. It is characterized by a proliferation of epidermal keratinocytes and a failure of the maturation of these cells in the formation of normal keratin. It affects 2% of the white population at some time in their life and there are important differences between different ethnic groups. In Europe, the prevalence varies from 1.5% in Croatia, to 4.8% in Norway. The evolution of the disease is unpredictable and has been shown to strongly affect the patient's quality of life (SR Rapp et al., Br. J. Dermatol. 145 , 610-616 (2001)).

The exact cause of psoriasis with involvement Dermal is unknown. It seems that, about a certain predisposition genetics, exogenous factors would act that would make the disease manifest or regrowth. Among these are: trauma streptococcal infections; alterations endocrine such as puberty, menopause, postpartum, treatment estrogenic; metabolic factors such as hypocalcaemia or dialysis; psychogenic factors such as stress or alcoholism and drugs (systemic corticosteroids, aspirin, penicillin, nystatin, Nonsteroidal anti-inflammatory drugs or NSAIDs, etc.). Besides, the corticosteroid interruption can trigger a new outbreak of psoriasis

Psoriasis with dermal involvement is a chronic disease that has no definitive treatment. Current medical treatment depends on the type of injury, location and age of the patient (R. Gniadecki et al., Acta Derm. Venereol. 82 , 401-410 (2002)). We will highlight the following therapeutic possibilities:

Topical corticosteroids have actions anti-inflammatory, anti-proliferative, immunosuppressive and vasoconstrictors The cutaneous side effects are stretch marks, skin atrophy, ecchymosis, perioral dermitis, rosacea, acne, allergic contact dermatitis, wound healing delays, hypertrichosis, glaucoma, folliculitis, miliaria and hypopigmentation, among others. Systemic corticosteroids are allowed in cases. of severe psoriasis.

Ditranol (anthralin) is effective in the Psoriasis treatment but should be used with caution since it has two important disadvantages. The first is that it produces a purple stain on the clothes and on the skin surrounding the psoriatic lesions The second is that it is a skin irritant unaffected and, if used at excessive power, will produce pain, erythema and vesicle formation.

Preparations with coal tar They are currently used much less. His main problem lies in that they have a strong smell and are also very dirty.

Calcipotriol is an analogue of vitamin D (CM Popescu et al., Arch. Dermatol. 136 (12) , 1547-1549 (2000)) which presents as advantages, compared to other topical preparations, its ease of use and its lack of effects on dermal collagen. However, although calcipotriol has antipsoriatic properties, it does not whiten the lesions completely, and in some patients it does not provide any benefit.

Phototherapy is performed by irradiating the skin with midrange ultraviolet radiation (UVB). The disadvantage of this treatment is that it takes time and patients have to go to specialized centers.

Photochemotherapy (PUVA) (topical or systemic) it consists of the topical or systemic use of a photosensitizer (8-MOP), with subsequent irradiation of the skin with GRAPE. This treatment is effective, but should be reserved for widespread plaque psoriasis or those that relapse quickly after topical treatments.

Acitretin is a retinoid that shows effects beneficial in psoriasis. Side effects include cheilitis and xeroderma and its prolonged use may cause hyperostosis and metaphysis closure in children and calcification of ligaments in adults. Hypertriglyceridemia is common.

Methotrexate is an effective medication to treat psoriasis (B. Kumar et al., Int. J. Dermatol. 41 (7) , 444-448 (2002)). However, a proportion of patients develop a feeling of nausea and lethargy 48 hours after the dose is administered. The main side effects include gastrointestinal ulceration and bone marrow depression, among others. In addition, this compound is hepatotoxic and can cause liver fibrosis, particularly after prolonged treatments.

Cyclosporine is the first drug used in psoriasis based on knowledge of disease pathogenesis rather than empirical (WP Gulliver, Cutis 66 (5) , 365-369 (2000)). Although it is effective in curing psoriasis, the most serious side effects include hypertension and nephrotoxicity and, for this reason, it is necessary to carefully monitor, particularly, renal function.

Glycosaminoglycans are biomolecules high molecular weight polymers found mainly in living organisms, where they develop Different physiological functions.

Chondroitin sulfate is a sulfated glycosaminoglycan with a polymeric structure characterized by a unit of a repeating disaccharide, consisting of N- acetylgalactosamine and glucuronic acid. The majority of N- acetylgalactosamine residues are sulfated.

Chondroitin sulfate from cartilaginous tissue is found mainly in two isomeric forms that differ in the position of the sulfate group present in the N- acetylgalactosamine residue. Chondroitin 4-sulfate (chondroitin sulfate A) containing mainly the disaccharide unit [-> 4) - O - (β-D-glucopyranosyluronic acid) - (1-> 3) - O - (2- N -acetamido -2-deoxy-? -D-galactopyranosyl-4-sulfate) - (1->] and chondroitin 6-sulfate (chondroitin sulfate C), which contains the disaccharide unit [-> 4) - O - (\ beta-D-glucopyranosyluronic acid) - (1-> 3) - O - (2- N -acetamido-2-deoxy-β-D-galactopyranosyl-6-sulfate) - (1->].

When in the memory of the present invention speaks of chondroitin sulfate, refers to chondroitin 4-sulfate, chondroitin 6-sulfate, chondroitin sulfate with some of the disaccharide units that are Repeat not sulfated, chondroitin sulfate with some of the Repeated disaccharide units polysulfated, chondroitin sulfate with the polysulfated repeating disaccharide unit, and to  The mixtures of them.

The use of chondroitin sulfate to treat various diseases has been described, for example, in the treatment of cardiovascular diseases (M. Morrison et al. US 3895106), however, the most widespread use of chondroitin sulfate is in the treatment of osteoarthritis. (osteoarthritis), which is characterized by joint dysfunction, with decrease and loss of cartilage (MG Lequesne, Rev. Rhum. Eng. Ed., 61 , 69-73 (1994), P. Morreale et al., J. Rheumatology 23 , 1385-1391 (1996) and G. Verbruggen et al., Osteoarthritis Cart., 6 (Supplement A), 37-38 (1998)).

Chondroitin sulfate that is commonly used in therapy it is in the form of sodium salt.

O. Olsen et al. (WO 01/83707) disclose a process for producing antiangiogenic, anti-inflammatory, lysozymic and / or anticolagenolytic fractions and / or collagen and / or chondroitin sulfate from chondrocytes grown in vitro . In the patent application a procedure is claimed to treat or prevent psoriasis using chondroitin sulfate obtainable from chondrocytes cultured in vitro , but in said patent application it is not described how to extract said chondroitin sulfate and therefore nothing is mentioned about of its characteristics and activity.

It is known that the structure of a chondroitin sulfate varies depending on the animal species, the tissue from which Proceed and the procedure for obtaining.

It is also known (M. Morrison et al. US 3895106) that differences in the activity of different chondroitin sulfates may be due both to differences in the process of obtaining and to the use of different starting material.

In fact, O. Olsen et al. (WO 01/83707) consider chondroitin sulfate obtainable from cultured chondrocytes, as a new product, since the claim is of the "product by process" type (new product definable and claimed by its method of production).

So far it has not been described described use of chondroitin sulfate, which comes from a hydrolysis enzymatic animal cartilage, in the treatment of psoriasis with dermal involvement.

From all that has been said it follows that the provide a useful drug in the treatment of psoriasis with dermal involvement, without the inconvenience or side effects of current therapies, is still a major problem of the therapy.

Explanation of the invention.

Unexpectedly, it has been observed that the Chondroitin Sulfate, which comes from an enzymatic hydrolysis of Animal cartilage, is useful in the treatment of psoriasis with dermal involvement Thus, the present invention relates to use of alkali metal or alkaline earth metal chondroitin sulfate, which comes from an enzymatic hydrolysis of animal cartilage, for the preparation of a medicine for the treatment or prevention of psoriasis with dermal involvement in a mammal.

In a preferred embodiment the animal cartilage It is bovine cartilage, pig or cartilaginous fish.

In a more preferred embodiment the chondroitin Alkali metal sulfate is chondroitin sodium sulfate.

More preferred is sodium chondroitin sulfate which has an average molecular weight between 10,000 and 40,000 daltons.

Similarly, chondroitin is more preferred. sodium sulfate having an average molecular weight comprised between 10,000 and 20,000 daltons.

In an even more preferred embodiment the Chondroitin Sodium Sulfate having an average molecular weight between 10,000 and 20,000 daltons, it has a content in sulfur between 5% and 7% weight / weight, based anhydrous

In a particularly preferred embodiment the medication is adapted for oral administration., which comprises 200 to 3,000 mg of chondroitin sodium sulfate per day.

Likewise, in one embodiment especially Preferred the drug is adapted for topical administration.

Chondroitin sulfate can be obtained from of cartilaginous tissues of animals, such as tracheas of cattle or pigs and cartilaginous shark skeleton.

Chondroitin Sodium Sulfate can be prepared following procedures described in the literature (A. D. Nusimovich and F. J. Vila, ES 547769).

The other alkaline and alkaline earth salts are can be obtained from chondroitin sodium sulfate by cation exchange sodium procedure corresponding, following chemical procedures conventional.

To use in the treatment or prevention of psoriasis with dermal involvement, metal chondroitin sulfate alkaline or alkaline earth of the present invention is formulated in suitable pharmaceutical compositions, using techniques and conventional excipients, such as those described in Remington's Pharmaceutical Science Handboock, Mack Pub. Co., N.Y., USA.

The pharmaceutical compositions of the invention they can be administered to the patient in required doses. The administration of the compositions can be effected by different routes, for example, oral, intravenous, intraperitoneal, intraarticular, subcutaneous, intramuscular, topical, intradermal or intranasal The pharmaceutical compositions of the invention include a therapeutically effective amount of chondroitin sulfate of alkali metal or alkaline earth metal that comes from hydrolysis enzymatic animal cartilage, said amount depending on many factors, such as the patient's physical condition, age, sex, particular compound, route of administration and others factors well known in the art. In addition, it will be understood that said dosage of active compound can be administered in single or multiple dose units to provide the effects Desired therapeutic. If desired, other agents may be used. Therapeutics together with those provided herein invention.

The chondroitin sulfate of the invention is preferably administered to the patient by means of a vehicle pharmaceutically acceptable. Such vehicles are well known in the technique and will generally be in solid or liquid form. Between pharmaceutical preparations in solid form that can Prepared in accordance with the present invention include powders, mini granules (pellets), tablets, dispersible granules, capsules, seals, suppositories and other solid galenic forms. Liquid form preparations include solutions, suspensions, emulsions, microspheres and nanoparticles. Be also contemplate the preparations of solid forms that are desired convert, immediately before being used, into preparations in liquid form for oral, parenteral or oral administration intraarticular Such liquid forms include solutions, suspensions and emulsions.

An advantage that can be obtained with the invention compared to the use of other therapies in the Treatment of psoriasis with dermal involvement, is that, Chondroitin sulfate is devoid of harmful effects to gastric, hepatic and renal level, and its use can be maintained for years without side effects.

Another advantage of using chondroitin sulfate that comes from an enzymatic hydrolysis of animal cartilage, lies in the ease of preparing said chondroitin sulfate from an affordable material such as animal cartilage, following a procedure well established in the literature. Obtaining an alternative chondroitin sulfate by culturing chondrocytes in vitro would be economically unfeasible, due to the large number of chondrocyte colonies that would be necessary to isolate a small amount of chondroitin sulfate.

Brief description of the figures

Figure 1 is a representative image of a longitudinal section of a dermal biopsy corresponding to a psoriatic patient before treatment with chondroitin sulfate (pre-treatment); Y

Figure 2 corresponds to a longitudinal section of a dermal biopsy corresponding to the same patient in the Figure 1 after chondroitin sulfate treatment (post-treatment). Staining by hematoxylin-eosin evidences the reduction of epidermal hyperplasia and vascular tortuosity caused by the Chondroitin sulfate treatment.

Detailed description of the invention

The following examples are merely illustrative and do not represent a limitation of the scope of the present invention

Example 1 Tablets

The tablets were prepared following conventional procedures

Formula by compressed: Chondroitin Sodium Sulfate ( 13,000-18,000 daltons) 400.0 mg Avicel PH 200 292.0 mg 200 spray 1.0 mg Magnesium stearate powder 7.0 mg

Example 2 Study in psoriatic patients treated with chondroitin sulfate Methodology. Description of the study

The study was conducted in 11 psoriatic patients 800 mg of orally administered daily Chondroitin Sulfate (two tablets of Example 1, per day), during A period of 2 months. The parameters determined at the beginning and At the end of the treatment they were the following:

one.-

Clinical assessment of the lesions dermal

2.-

Histopathological analysis of dermal biopsies

1.- Clinical assessment of dermal lesions

Basically, the process that occurs in the skin in the case of psoriasis and the effect that was observed after Chondroitin sulfate administration is as follows:

A) In psoriatic patients, the skin in the lesions becomes thicker due to the large increase in the number of epidermis cells The renewal of the external cells of the skin (epidermis) occurs in 4 days, instead of 25-30 usual days (seven times faster), for this accumulates the layers of dead skin, which detach in scale shape

After administration of chondroitin sulfate, the Biopsies examined showed a decrease in hyperkeratosis, that is, decreased the number of keratinocytes or skin cells that cause the characteristic plaques of the psoriasis. There was a general improvement in the desquamation of the injuries

B) In patients with psoriasis, the skin cells do not mature and do not protect properly, losing moisture from injuries.

After administration of chondroitin sulfate, observed a dramatic increase in the hydration of injuries

C) The skin of patients with psoriasis it has thicker and longer capillaries than normal skin, entangled over themselves, and blood flows in more quantity, by the plates appear reddened. The skin is inflamed and Increase the number of cells in the immune system.

After administration of chondroitin sulfate, some of the patients described a decrease in the redness and burning sensation that occurs in the injury.

2.- Histological - pathological study

Histopathological analysis of 22 was performed dermal biopsies corresponding to the 11 psoriatic patients before and after treatment with chondroitin sulfate.

Parameters evaluated Quantitative variables

The total thickness of the epidermis, the maximum thickness from the base layer) to the beginning of the layer cornea and the maximum thickness of the cornea layer. It was also determined the number of cells in proliferation cycle.

The pre and post-treatment for each patient, establishing a percentage reduction figure for each variable or increased thickness after treatment administration.

Semiquantitative variables

The degree of activity of the psoriasis based on its diagnostic clues (hyperplasia epidermal or acanthosis, parakeratosis, neutrophilic exocytosis and tortuosity of capillaries of the papillary dermis). Establishment four different grades (0, 1, 2 and 3) and the differences were evaluated Pre and post treatment.

Qualitative variables

The presence of orthokeratosis was determined (normal keratinization of the skin) or parakeratosis (abnormal keratinization of the skin) in dermal biopsies.

Statistic analysis

A statistical analysis of the results obtained by means of an analysis of variance (ANOVA) was performed, considering differences that presented a p less than 0.05.

Results Thickness of the epidermis

In the three variables studied (thickness total epidermal, maximum thickness from the basal layer to the beginning of the cornea layer and maximum thickness of the cornea layer) observed an evident decrease in thickness in most of the patients, the maximum percentage of decrease being 61, 69 and 62%, respectively (see Tables 1, 2 and 3). The average decrease was greater in total epidermal thickness and thickness since the basal layer until the beginning of the corneal layer (30%) than in the thickness of the corneal layer (15%). Therefore, the increase in thickness of the epidermis presented by psoriatic patients due to a greater number of keratinocytes or cells of the epidermis, was reduced notably for chondroitin sulfate treatment (see Figures 1 and 2).

TABLE 1 Maximum epidermal thickness (* p < 0.05)

one

TABLE 2 Maximum basal-cornea thickness (* p < 0.05)

2

TABLE 3 Maximum corneal thickness (* p <0.05)

3

Total epidermal thickness measurement varied between 300 µm and 496 µm before (pre) treatment and between 156 µm and 400 µm after it (post) (see Table 1). He maximum basal-corneal thickness varied between 196 µm and  400 µm (pre) and between 104 µm and 344 µm (post) (see Table 2). The maximum thickness of the corneal layer varied between 32 µm and 160 \ mum (pre) and between 28 \ mum and 160 \ mum (post) (see Table 3).

Cell proliferation rate

As seen in Table 4, the results revealed that chondroitin sulfate treatment reduced the number of cells (keratinocytes) in the cycle of proliferation, the average value being a 28% decrease. By consequently, the high number of keratinocytes in division that characterizes psoriatic plaques decreased with administration Chondroitin Sulfate

TABLE 4 Proliferation Index (* p < 0.05)

4

Degree of psoriasis activity

Table 5 details the differences. found in the degree of psoriasis activity, which They were also very remarkable.

TABLE 5 Degree of psoriasis (* p <0.05)

5

Presence of orthokeratosis or parakeratosis

At the beginning of treatment, 9 patients presented extensive parakeratosis (PK, abnormal keratinization of the skin) and 2 patients showed orthokeratotic keratinization (OK, normal keratinization of the skin) predominant with focal areas of PK. At the end of treatment with chondroitin sulfate, in 6 of those 9 cases described with initial PK, predominant OK was observed with PK focal point (see Table 6).

TABLE 6 Orthokeratosis (OK) / Parakeratosis (PK)

6

Conclusions

The 11 psoriatic patients treated with Chondroitin sulfate (800 mg / day) for 2 months presented a dramatic improvement of your dermal lesions at the clinical level in a 100% of cases. The results of the histopathological study of the biopsies revealed an improvement in the different parameters determined in 70% of patients. Specifically, it was observed a decrease in the thickness of the epidermis, as well as a reduction in the keratinocyte cell proliferation index or skin cells The degree of psoriasis activity also decreased It is important to note that, at histological level, 30% remaining patients did not get worse with treatment with Chondroitin Sulfate

These effects of chondroitin sulfate observed in psoriatic patients they were corroborated with the assessment of same patients, which was also very positive and satisfactory

Therefore, it can be concluded that, in patients affected by psoriasis, oral administration of 800 mg / day Chondroitin sulfate significantly improves injuries dermal produced by said disease, with an excellent profile of security.

Claims (9)

1. Use of alkali metal chondroitin sulfate or alkaline earth, which comes from an enzymatic hydrolysis of animal cartilage, for the preparation of a medicine for treatment or prevention of psoriasis with dermal involvement in a mammal. 2. Use according to claim 1, wherein the Animal cartilage is bovine, pig or fish cartilage cartilaginous 3. Use according to claim 2, wherein the Chondroitin alkali metal sulfate is chondroitin sulfate sodium. 4. Use according to claim 3, wherein the Chondroitin Sodium Sulfate has an average molecular weight between 10,000 and 40,000 daltons. 5. Use according to claim 3, wherein the Chondroitin Sodium Sulfate has an average molecular weight between 10,000 and 20,000 daltons. 6. Use according to claim 5, wherein the Chondroitin Sodium Sulfate has a sulfur content comprised between 5% and 7% weight / weight, on an anhydrous basis. 7. Use according to any of claims 1 to 6, in which the drug is adapted for administration oral. 8. Use according to any of claims 1 to 6, in which the drug is adapted for administration topical 9. Use according to claim 7, wherein the oral administration comprises 200 to 3,000 mg of chondroitin sodium sulfate per day.